Association of TIMP4 gene variants with steroid-induced osteonecrosis of the femoral head in the population of northern China

BACKGROUND: In clinical treatment, the use of steroid hormones is an important etiological factor of non-traumatic osteonecrosis of the femoral head (ONFH) risk. As an endogenous inhibitor of matrix metalloproteinases (MMPs) in the extracellular matrix, the expression of tissue inhibitors of metalloprotease-4 (TIMP4) plays an essential role in cartilage and bone tissue damage and remodeling, vasculitis formation, intravascular thrombosis, and lipid metabolism. METHODS: This study aimed to detect the association between TIMP4 polymorphism and steroid-induced ONFH. We genotyped seven single-nucleotide polymorphisms (SNPs) in TIMP4 genes and analyzed the association with steroid-induced ONFH from 286 steroid-induced ONFH patients and 309 normal individuals. RESULTS: We performed allelic model analysis and found that the minor alleles of five SNPs (rs99365, rs308952, rs3817004, rs2279750, and rs3755724) were associated with decreased steroid-induced ONFH (p = 0.02, p = 0.03, p = 0.04, p = 0.01, p = 0.04, respectively). rs2279750 showed a significant association with decreased risk of steroid-induced ONFH in the Dominant and Log-additive models (p = 0.042, p = 0.028, respectively), and rs9935, rs30892, and rs3817004 were associated with decreased risk in the Log-additive model (p = 0.038, p = 0.044, p = 0.042, respectively). In further stratification analysis, TIMP4 gene variants showed a significant association with steroid-induced ONFH in gender under the genotypes. Haplotype analysis also revealed that “TCAGAC” and “CCGGAA” sequences have protective effect on steroid-induced ONFH. CONCLUSION: Our results indicate that five TIMP4 SNPs (rs99365, rs308952, rs3817004 rs2279750, and rs3755724) are significantly associated with decreased risk of steroid-induced ONFH in the population of northern China.